Hemostatic complications of cardiac surgery often occur for reasons that are not well understood. Despite efforts to limit blood loss and blood product transfusion, cardiac surgery patients consume 10-20% of the nation?s blood supply. Postoperative thrombotic events, such as coronary graft occlusion, are often unpredictable, and cause appreciable morbidity, resource utilization, such as need for additional revascularization. Many risk factors for these complications have been identified; among these, it is known that activation of the coagulation system occurs during cardiopulmonary bypass (CPB) and is responsible for mediating substantial postoperative hemostatic impairment. Although contact system activation unquestionably occurs during CPB, the role of the extrinsic system has not been characterized. Extrinsic system activation does occur on CPB, and may be the major contributor to thrombin generation. Furthermore, genetic variants within the genes for tissue factor, factor VII, and tissue factor pathway inhibitor have been described, and many of these significantly influence the activity of their respective protein gene products. However, the impact of these polymorphisms in contributing toward extrinsic system activation during CPB is undescribed. The overall goal of this study is to evaluate the contribution of extrinsic system variation toward observed variability in thrombin generation and impairment of hemostasis following CPB, and identify specific genetic variants in the extrinsic system that may place patients at increased risk for coagulation system abnormalities following CPB. This understanding will assist clinicians in identifying cardiac surgery patients at increased risk for hemostatic abnormalities, and target novel therapies toward those patients most likely to benefit. The project will make extensive use of data in the Vanderbilt Cardiac Surgery Registry, a valuable database of genetic and clinical data presently being prospectively collected on elective adult cardiac surgery patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL004476-05
Application #
6993646
Study Section
Special Emphasis Panel (ZHL1-CSR-F (O1))
Program Officer
Mondoro, Traci
Project Start
2002-01-07
Project End
2006-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
5
Fiscal Year
2006
Total Cost
$151,279
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Pretorius, Mias; Donahue, Brian S; Yu, Chang et al. (2007) Plasminogen activator inhibitor-1 as a predictor of postoperative atrial fibrillation after cardiopulmonary bypass. Circulation 116:I1-7
Bruehl, Stephen; Chung, Ok Y; Donahue, Brian S et al. (2006) Anger regulation style, postoperative pain, and relationship to the A118G mu opioid receptor gene polymorphism: a preliminary study. J Behav Med 29:161-9
Sambasivan, Arathi; Tibble, Adam; Donahue, Brian S (2006) Low arterial saturation is associated with increased sensitivity to activated protein C in children with congenital heart disease. J Cardiothorac Vasc Anesth 20:38-42
Donahue, B S; Gailani, D; Mast, A E (2006) Disposition of tissue factor pathway inhibitor during cardiopulmonary bypass. J Thromb Haemost 4:1011-6
Donahue, Brian S (2004) The response to activated protein C after cardiopulmonary bypass: impact of factor V leiden. Anesth Analg 99:1598-603, table of contents
Donahue, Brian S; Byrne, Daniel W; Gailani, David et al. (2003) Tissue factor and platelet glycoprotein Ib-alpha alleles are associated with age at first coronary bypass operation. Anesthesiology 99:1287-94
Donahue, Brian S; Gailani, David; Higgins, Michael S et al. (2003) Factor V Leiden protects against blood loss and transfusion after cardiac surgery. Circulation 107:1003-8
Donahue, Brian S (2002) Thrombosis after deep hypothermic circulatory arrest with antifibrinolytic therapy: is factor V leiden the smoking gun? Anesthesiology 97:760-1; author reply 761